The skeleton is a preferential site of metastasis for a variety of cancers at their advanced stages. Once the tumor spreads to bone, it can become unresponsive to standard therapeutic treatments and currently there is no effective treatment for bone metastases. The diagnostic imaging of bone metastases is most commonly performed with 99mTc-MDP whole-body gamma scintigraphy, but its findings are often nonspecific, and additional imaging procedures are required to make a final diagnosis. Thus we propose to address the hypothesis that the sensitivity and specificity of bone metastasis detection will be significantly improved if kinetically inert bone-seeking macrocyclic tetraamine complexes can be used for multimodality imaging diagnosis of bone metastases based upon the pharmacological mechanism of bisphosphonates against bone metastases. The three specific aims of this proposal are: (I) to synthesize and characterize bone- seeking macrocyclic chelators with a methylene-phosphonate or bisphosphonate motif and investigate their coordination chemistry with Cu(ll), Lu(lll), and Gd(lll); (II) to prepare and evaluate MCu and 177Lu labeled complexes as PET/SPECT imaging agents specifically for the detection and in situ monitoring of bone metastases; (III) to prepare and investigate cold gadolinium complexes and identify optimal candidates as MRI bone-contrast agents for diagnostic imaging of bone metastases. In Specific Aim (I), the synthesis of proposed iigands is based on the selective protection- functionalization-deprotection of the parent macrocyclic tetramine Cyclen using standard organic synthetic methods and peptide coupling procedures. Metal complexes of these Iigands will be prepared and characterized spectrally and structurally. The thermodynamic stability constants and-the kinetic stability of the complexes will be then determined to identify promising ligand candidates for follow-up biological studies. In Specific Aims (II) and (III), the selected Iigands will be labeled with Cu and Lu radionuclides and evaluated for their in vivo stability and tissue distribution as compared to the clinical standard bone-scan agent, 99mTc- MDP; the proton NMR T1 relaxivities will be determined for the cold Gd complexes in vitro. The most promising compounds will be evaluated with an intra-femoral bone metastasis model by small animal imaging facilities in the Cancer Imaging Program of the UT Southwestern Medical Center at Dallas. [unreadable] [unreadable] [unreadable]